Dry eye disease (DED) is one of the most common and discomforting eye disorders. It has been defined as a multifactorial ocular surface disease more prevalent in women and the elderly. DED is associated with symptoms of discomfort, visual disturbance, tear film instability and inflammation of the ocular surface leading to potential damage to the ocular surface tissues (Research in Dry Eye DEWS Report 2007). The pro-inflammatory milieu is characterized by increased levels of cytokines and chemokines in the tear film, cornea and conjunctiva, and increased autoreactive T-cell infiltration of the conjunctival epithelium and sometimes lacrimal gland (Pflugfelder et al., 1999; de Paiva et al., 2009a; Massingale et al., 2009); as reviewed by Stern and colleagues (Stern et al., 2010; Stern et al., 2013). Alteration of the tear film composition (mucins, lipids, proteins) and decreased volume lead to tear film abnormalities that contribute to the disease cycle.
Subjecting mice to a controlled environment of desiccating stress (DS) results in ocular surface pathology reminiscent of human DED in patients in many respects (Dursun et al., 2002; de Paiva et al., 2006b; Niederkorn et al., 2006; de Paiva et al., 2009a). As of today, this model represents the best characterized animal model to study DED.
Integrins are heterodimeric glycoproteins consisting of one α- and one β-subunit. Expressed on the cell surface of leukocytes, integrins play a role in their recruitment to sites of inflammation. The association of a specific α- and β-subunit determines the ligand specificity of the integrin. The α4 integrin subunit (CD49d) is a constituent of Very Late Antigen-4, VLA-4 (integrin α4β1; CD49d/CD29) and α4β7 (CD49d/CD103). In the case of integrin α4β1, the corresponding ligands are the immunoglobulin superfamily adhesion molecule vascular cell adhesion molecule 1 (VCAM-1) on vascular endothelial cells and the extracellular matrix glycoprotein fibronectin, which are responsible for the homing, trafficking, differentiation, priming, activation, proliferation and survival of integrin α4β1 expressing cells. Integrin α4β1 is expressed on lymphocytes, monocytes, macrophages, NK cells and eosinophils. Integrin α4β7 and its corresponding ligand, MAdCAM (Mucosal Addressin Cell Adhesion Molecule-1), regulate leukocyte trafficking to the gut, but their involvement in DED cannot be ruled out.
Natalizumab, an antibody directed against the integrin α4 subunit, has been shown to profoundly inhibit inflammation and improve clinical outcomes in both multiple sclerosis (Cross and Naismith, 2014) and Crohn's disease (Cohen et al., 2014) which are also T cell mediated pathologies. Lifitegrast, a small molecule antagonist, directed against a different adhesion molecule (LFA-1, integrin αLβ2), has been shown to reduce corneal staining and improve symptoms when delivered topically to dry eye patients (Sheppard et al., 2014). Furthermore, a specific small molecule antagonist to integrin α4β1, BIO-8809, had been shown to decrease corneal fluorescein staining, conjunctival T cell infiltrates and TNFα expression in cornea and conjunctiva in a murine dry eye model (Ecoiffier et al., 2008). Taken together these considerations provided a rationale for further exploring the blockade of integrin α4 in an animal model of DED.